Primary biliry cirrhosis (PBC) is a disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative presumably autoimmune destruction of septal and interlobular bile ducts. In controlled trials neither penicillamine nor azathioprine have unequivocally improved survival or slowed the progression of the disease. Because certain other autoimmune diseases appear to respond favorably to alkylating agents but not to azathioprine, a controlled trial of chlorambucil for the treatment of PBC has been initiated. Twenty-four patients (23 women, 1 man; ages 34-63) have been admitted to this trial: 13 were randomized to chlorambucil therapy and 11 to the control group. All patients have been followed for at least one year and some for as long as four years. One of the control patients but none of the treated patients has died. Serum bilirubin levels have remained stable in treated patients, but have risen in most of the untreated patients. IgM levels have decreased significantly in the treated patients but have risen in the untreated patients. Liver biopsies have revealed a marked dimunition in hepatic inflammation among the treated patients.